Noninvasive applied force / optical glucose concentration determination analyzer apparatus and method of use thereof

ABSTRACT

The invention comprises an applied force-optic analyzer used to determine a sample constituent concentration, a physical measure of the sample, and/or a state of the sample. The analyzer comprises: an electro-mechanical transducer affixed to skin of a subject; a controller, the controller providing a voltage waveform to the electro-mechanical transducer driving displacement of the skin and inducing a pressure wave into the skin; and a spectrometer interfaced to a sample site of the skin, the spectrometer comprising a set of sources and a set of detectors, where the controller is configured to collect signal from the set of detectors as a function of timing of the voltage waveform and apply a calibration model to the signal to determine the analyte concentration.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application:

-   -   claims the benefit of U.S. provisional patent application No.        62/838,283 filed Apr. 24, 2019;    -   claims the benefit of U.S. provisional patent application No.        62/838,838 filed Apr. 25, 2019; and    -   claims the benefit of U.S. provisional patent application No.        62/846,521 filed May 10, 2019.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to noninvasively determining glucoseconcentration in a living body using an applied force to the body incombination with use of an optical analyzer, such as avisible/near-infrared noninvasive glucose concentration determinationanalyzer.

Discussion of the Prior Art

There exists in the art a need for noninvasively determining glucoseconcentration in the human body.

SUMMARY OF THE INVENTION

The invention comprises an applied force-optical glucose concentrationanalyzer apparatus and method of use thereof.

DESCRIPTION OF THE FIGURES

A more complete understanding of the present invention is derived byreferring to the detailed description and claims when considered inconnection with the Figures, wherein like reference numbers refer tosimilar items throughout the Figures.

FIG. 1 illustrates use of an applied force-optic analyzer;

FIG. 2 illustrates a noninvasive analyzer;

FIG. 3A illustrates an applied force system, FIG. 3B illustrates atransducer, FIG. 3C illustrates transducer movement normal to an opticalaxis, FIG. 3D illustrates a z-axis transducer, and FIG. 3E illustrates amulti-axes off-center spinning mass transducer;

FIG. 4A illustrates spectrometer components, FIG. 4B illustrates anaffixing layer, and FIG. 4C illustrates a coupling fluid enhancedaffixer;

FIG. 5A illustrates a force system coupled to a spectrometer and FIG. 5Billustrates a force system embedded in a spectrometer;

FIG. 6 illustrates photons interacting with applied force wave(s) intissue;

FIG. 7 illustrates absorbance of skin constituents;

FIG. 8 illustrates detector selection;

FIG. 9 illustrates changing detector selection with tissue change;

FIG. 10A illustrates a transducer force applicator and FIG. 10B and FIG.10C illustrate transducer force detectors in lines and arcsrespectively;

FIG. 11A illustrates radial optical detection of force waves, FIG. 11Billustrates an array of optical detectors, and FIG. 11C illustrates arcsof optical detectors; and

FIG. 12 illustrates optical probes observing tissue modified by forcewaves in a noninvasive glucose concentration determinationsystem/analyzer.

Elements and steps in the figures are illustrated for simplicity andclarity and have not necessarily been rendered according to anyparticular sequence. For example, steps that are performed concurrentlyor in different order are illustrated in the figures to help improveunderstanding of embodiments of the present invention.

PROBLEM

There remains in the art a need for a noninvasive glucose concentrationanalyzer.

DETAILED DESCRIPTION OF THE INVENTION

The invention comprises an applied force-optic analyzer used todetermine a sample constituent concentration, a physical measure of thesample, and/or a state of the sample. The analyzer comprises: anelectro-mechanical transducer affixed to skin of a subject; acontroller, the controller providing a voltage waveform to theelectro-mechanical transducer driving displacement of the skin andinducing a pressure wave into the skin; and a spectrometer interfaced toa sample site of the skin, the spectrometer comprising a set of sourcesand a set of detectors, where the controller is configured to collectsignal from the set of detectors as a function of timing of the voltagewaveform and apply a calibration model to the signal to determine theanalyte concentration.

Herein, generally, when describing an optical portion of the appliedforce-optic analyzer, a z-axis is aligned with a mean direction of thephotons in a given sub-portion of the analyzer, such as along alongitudinal path of the photons into skin of a subject, and x- andy-axes form a plane perpendicular to the z-axis, such as at an interfacepoint of incident photons into the skin of the subject. At the point ofcontact of the applied force-optic analyzer with the biological sample,the z-axis is normal/perpendicular to the sample and the x/y-planetangentially contacts the sample. For instance, the light movesdominantly along the z-axis along vectors approaching perpendicular toan upper arm of a subject or a patient and the x/y-plane tangentiallytouches the upper arm along the z-axis. In particular cases, a secondx,y,z-axis system is used to describe the sample itself, such as az-axis being along the longitudinal length of a body part, such as alonga digit or a finger or along the length of an arm section and thex/y-plane in this case is a cross-section plane of the body part.

A sample is optionally any material responding to an applied physicalforce in a manner observed by a probing optical system. However, forclarity of presentation and without loss of generality, the sample isdescribed as a person, subject, patient, and/or a living tissue, such asskin and/or a portion of a human or animal. While the analyzer isdescribed as a noninvasive analyzer probing into and optionally throughthe outer layers of skin, the noninvasive analyzer is optionally used asand or in conjunction with a minimally invasive glucose concentrationanalyzer and/or in conjunction with an invasive glucose concentrationanalyzer.

Herein, an illumination zone and/or an imaging zone is a point, region,or area of intersection of the illumination/imaging beam and/or pulsewith an incident surface of the sample to yield a spectrum and/or animage of a desired volume of the sample. Herein, a detection zone is apoint, region, or area of the sample sampled and/or visualized by one ormore detectors. Similarly, herein an applied force zone is an incidentpoint, region, or area of intersection at which an applied force isapplied to the sample and a detected force zone is a point, region, orarea of the sample interfacing with a force detector.

Applied Force-Optic Analyzer

Referring now to FIG. 1 , a noninvasive analysis system 100 using ananalyzer 110, such as an applied force-optic analyzer system isillustrated. Generally, an optional force system 200 is used to applyone or more applied forces, physical distortions, and/or force waves toa sample 300. The applied force travels with a wave front, as a wave, ina pattern of compression and rarefication, and/or as a travelingdisplacement through the sample 300 or portions thereof. With or withoutapplication of the force waves, a spectrometer 140 is used tononinvasively collect spectra of the sample 300 and photometricallydetermine one or more properties of the sample, such as a glucoseconcentration. As described infra, the applied force is optionally inthe form of an acoustic wave. However, the applied force is optionallyand preferably a physical displacement of a portion of skin of a person,where the physical displacement is caused by movement of a mechanicalobject relative to the body to yield a time varying displacement of skinand/or constituents of the skin by the mechanical object. As described,infra, a variety of force provider technologies are available tovariably displace the skin in a controlled manner. For clarity ofpresentation and without loss of generality, a transducer is used as anexample to represent an applied force section of the force system 200,where a transducer comprises a device that receives a signal/force inthe form of one type of energy and converts it to a signal/force inanother form. Again for clarity of presentation and without loss ofgenerality, a piezoelectric actuator is used to represent a transducerand an off-center spinning mass is used to represent a transducer.Hence, again for clarity of presentation and without loss of generality,a piezoelectric-optical analyzer or simply a piezo-optic analyzer, atransducer, and/or a transducer force applicator is used to describe anyand all applied force electromechanical sources in the force system 200.

Referring now to FIG. 2 , use of the analyzer 110 is described.Generally, the analyzer 110 is optionally calibrated using a reference310 and is used to measure a subject 320, where the subject 320 is anexample of the sample 300. Optionally and preferably, the analyzer 110and/or a constituent thereof communicates with a remote system 130 usinga wireless communication protocol 112 and/or a wired communicationprotocol.

Force System

Referring now to FIGS. 3 (A-E), the force system 200 is furtherdescribed. Generally, the force system 200 comprises a force deliverytransducer that directly and/or indirectly contacts the sample 300, suchas an outer skin surface 330 of the subject 320 and/or a patient. Thesubject 320 has many skin layers 340. For clarity of presentation, theskin layers 320 are represented as having a first skin layer, such as astratum corneum 342; a second skin layer, such as an epidermis 344 orepidermal layer; a third skin layer, such as a dermis 346 or dermislayer; and a fourth layer, such as subcutaneous fat 348 or asubcutaneous fat layer. It is recognized that skin is a complex organwith many additional layers and many sub-layers of the named layers thatvary in thickness and shape with time.

However, for clarity of presentation and without loss of generality, thestratum corneum, epidermis, dermis, and subcutaneous fat layers are usedto illustrate impact of the force delivery transducer on the skin layers340 of the subject 320 and how the applied force waves alter opticalpaths of probing photons in the spectrometer 140 of the analyzer 110 inthe noninvasive analysis system 100.

Still referring to FIG. 3A, at a first time, t₁, the tissue layers 340are in a first state. As illustrated, the tissue layers 340 are in acompressed state 340, such as a result of mass of the force system 200sitting on the skin surface 330, as a result of dehydration of thesubject 320, and/or as a result of a physiological and/or environmentalforce on the tissue layers 340 of the subject. At a second time, t₂, theforce system 200 applies a force wave 250 to the skin surface 330 of thepatient 320, which sequentially propagates into the stratum corneum 342,epidermis 344, dermis 346, and given enough force into the subcutaneousfat 348. In additional to the force wave propagating into the skinlayers 340 along the z-axis, the force wave propagates radially throughthe skin layers, such as along the x/y-plane of the skin layers. Asillustrated at the second time, t₂, as the force wave 250 propagatesinto the tissue layers 340, the tissue layers expand and/or rarefy, suchthat the thickness of the epidermis 344 and/or the dermis 346 layersexpands. The rarefication of the epidermis 344 and particularly thedermis 346 allows an increased and/or enhanced perfusion of blood 350into the rarefied layers. The increased prefusion increases waterconcentration in the perfused layers, increase and/or changes distancebetween cells in the perfused layers, and/or changes shapes of cells inthe perfused layers, such as through osmolarity induced changes inconcentration in and/or around blood cells, such as red blood cells.Generally, scattering coefficients of the epidermis layer and/orespecially the dermis layer changes, which is observed by thespectrometer 140 in the range of 400 to 2500 nm with larger changes atsmaller wavelengths in the visible, 400 to 700 nm, and/or near-infrared,700 to 2500 nm, regions. As illustrated at the third time, t₃, as theforce wave 250 continues propagation in the tissue layers 340, theperfusion 350 continues to increase, such as to a maximum perfusion. Asillustrated at the fourth time, t₄, after discontinuation of the forcewave 250, the skin layers 340 revert toward the initial state of thenon-force wave induced perfusion to a local minimum perfusion, which maymatch the initial perfusion, is likely higher than the initialperfusion, and is at times less than the initial perfusion due tochanges in state of the environment, such as temperature, and/orgeneralized state of the subject 320, such as hydration, localizedhydration of skin, such as due to food intake, insulin response to foodintake, exercise level, blood pressure, and/or the like. Generally, thetissue layers 340 of the subject increase in thickness and/or rarefyduring application of the transducer applied force wave 250 and decreaseand/or compress after termination of the transducer applied force wave250 to the skin surface 330 of the subject 320. The process of applyingthe force wave 250 is optionally and preferably repeated n times, wheren is a positive integer of greater than 1, 2, 5, 10, 100, 1000, or 5000times in a measurement period of an analyte of the subject 320, such asa glucose concentration. Generally, the cycle of applying the force wave250 results in a compression-rarefication cycle of the tissue thatalters an observed scattering and/or absorbance of probing photons inthe visible and near-infrared regions. The force wave 250 is optionallyand preferably applied as a single ping force in a tissue stateclassification step, as multiple pings in a tissue classification step,and/or as a series of waves during a tissue measurement step. Individualwaves of a set of force waves are optionally controlled and varied interms of one or more of: time of application, amplitude, period,frequency, and/or duty cycle.

Still referring to FIG. 3A and referring now to FIGS. 3 (B-D), a forcewave input element 210 of the force system 200 is illustrated. Asillustrated, the force wave input element 210 is equipped with one ormore transducers: a left transducer 221, a right transducer 222, a fronttransducer 223, a back transducer 224, a top transducer 225, and/or abottom transducer 226. For instance, the left and/or right transducers221, 222 move the force wave input element 210 left and/or right alongthe x-axis; the front and/or back transducers 223, 224 move the forcewave input element 210 forward and/or back along the y-axis; and/or thetop and bottom transducers 225, 226 move the force wave input element210 up and/or down along the z-axis along and/or into the skin surface330 of the subject 320, which moves the skin, skin layers 340, and/orskin surface 330 of the subject relative the spectrometer 140 and/or isa source of the force wave 250 moving, in the skin layers 340, along thez-axis into the skin, and/or radially outward from an interface zone ofthe force wave input element 210 of the force system 200. A transduceritself is optionally used as the force wave impulse element 210.Referring now to FIG. 3E, one or more off-center mass elements 230 isoptionally spun or rotated, such as with an electric motor, along one ormore of the x,y,z-axes to move the force wave input element 210 relativeto the skin surface 330 of the subject 320 resulting movement of theskin of the subject 320 relative to the spectrometer 140 and/or cyclingand/or periodic displacement of the tissue layers 340 of the subject 320due to movement of the force wave input element 210 resulting in theforce wave(s) 250. Generally, the force system 200 induces a movement ofa sampled zone of skin of the subject 320, applies a displacement of asampled zone of the skin of the subject 320, and/or applies apropagating force wave into and/or through a sample zone of tissuelayers 340 of the subject, where the sampled zone is probed usingphotons from the spectrometer 140 and/or is measured using a set ofdetection zone transducers, described infra. The force wave(s) areoptionally and preferably applied as a single input ping wave, a set ofinput ping waves, and/or are applied with a frequency of 0.01 Hz to 60Hz. Optionally and preferably, the force waves 250 are applied with afrequency greater than 0.01, 0.02, 0.05, 0.1, or 1 Hz. Optionally andpreferably, the force waves 250 are applied with a frequency of lessthan 200, 100, 50, 40, 30, or 20 Hz. Optionally and preferably, theforce waves 250 are applied with a frequency within 5, 10, 25, 50, or100 percent of 2, 4, 6, 8, 10, 12, 15, and 20 Hz.

Optical System

Referring now to FIG. 4A, the spectrometer 140 of the analyzer 110 isfurther described. The spectrometer 140 comprises a source system 400,which provides photons 452 in the visible and/or infrared regions to thesubject 320, such as via a photon transport system 450, at anillumination zone. After scattering and/or absorbance by the tissuelayers 340 of the subject 320, a portion of the photons are detected ata detection zone by a detector system 500. The source system 400includes one or more light sources, such as any of one or more of alight emitting diode, a laser diode, a black body emitter, and/or awhite light source, that emits at any wavelength, range of wavelengths,and/or sets of wavelengths from 400 to 2500 nm. Each source systemphoton source is optionally controlled in terms of time of illumination,intensity, amplitude, wavelength range, and/or bandwidth. The photontransport system 450 comprises any fiber optic, light pipe, airinterface, air transport path, optic, and/or mirror to guide the photonsfrom the light source to one or more illumination zones of the skinsurface 330 of the subject 320 and/or to guide the photons from one ormore detection zones of the skin surface 330 of the subject 320 to oneor more detectors of the detector system 500. Optionally and preferably,the photon transport system 450 includes one or more optical filtersand/or substrates to selectively pass one or more wavelength regions foreach source element of the source system 400 and/or to selectively passone or more wavelength ranges to each detector element of the detectorsystem 500. Herein, the reference 310 is optionally an intensity and/orwavelength reference material used in place of the sample and/or is usedin a optical path simultaneously measured by the analyzer 110.

Still referring to FIG. 4A and referring now to FIG. 4B and FIG. 4C, thesubject 320 optionally and preferably wears the analyzer 110 in thephysical form of a watch head, band, and/or physical element attached tothe body with a band and/or an adhesive. For example, the analyzer 110,the spectrometer 140, the source system 400, and/or the photon transportsystem 450 is optionally attached to the subject 320, such as at thewrist or upper arm, using thin affixing layer 460, such as a doublesided adhesive 462. Referring now to FIG. 4B, the double sided adhesive462 optionally contains an aperture 464 therethrough. The photons 452optionally and preferably pass through the aperture 452 to the skinsurface 330 of the subject. The force wave 250 optionally moves the skinsurface 330 through the aperture into intermittent contact with theanalyzer 110. Optionally, referring now to FIG. 4C, a thin affixinglayer 466, such as less than 1, 0.5, or 0.25 mm thick, is continuous innature in front of the incident surface and/or incident photon couplingzone and/or is continuous in nature in front of the detection zone,where photons exiting the skin surface 330 are detected by the detectorsystem 500. The affixing layer 466 is optionally permeated with a fluid,such as a coupling fluid, an air displacement medium, an opticalcoupling fluid, a fluorocarbon liquid, a fluorocarbon gel, an index ofrefraction matching medium, and/or any fluid that increases a percentageof photons from the source system 400 entering the skin surface 330compared to an absence of the fluid and/or is any fluid that increases apercentage of photons from the tissue layers 340 exiting the detectionzone and reaching the detector system 500 as compared to a case wherethe fluid is not embedded into the affixing layer. Hence, the affixinglayer serves several purposes: attaching the analyzer or a portionthereof to the skin surface 330 of the subject 320, coupling forces fromthe force system 200 to the skin surface 330 of the subject 320, forminga constant sampling interface location on the skin surface 330 of thesubject, and/or altering a coupling efficiency, angular direction,and/or reproducibility of coupling of photons enter the skin of thesubject 320 and/or exiting the skin surface 330.

Coupled Force System/Spectrometer

Referring now to FIG. 5A and FIG. 5B, the force system 200 isillustrated working in conjunction with the spectrometer 140. Referringnow to FIG. 5A, the analyzer 110 is illustrated with the force system200 being attached to and/or within 1, 2, 3, 5, 10, 20, or 50 mm of thespectrometer 140. Referring now to FIG. 5B, the analyzer 110 isillustrated with the force system 200 being integrated into thespectrometer 140, such as within 20, 10, 5, 2, or 1 mm of the sourcesystem 400 of the analyzer 110 and/or in a single housing unit of theanalyzer 110.

Several examples are provided that illustrate how the force system 200alters the tissue layers 340 of the subject 320 and how a selection ofdetected signals from the spectrometer 140 is performed as a function oftime and respective radial separation between the one or moreillumination zones and the one or more detection zones, such as usingwater signal, fat signal, and/or protein signal to determine the correctdetection signals to use for noninvasive glucose concentrationdetermination.

Example I

Referring now to FIG. 6 , a first example of the analyzer 110 using theforce system 200 and the source system 400 at the same time and/orwithin less than 60, 30, 15, 10, 5, or 1 second of each other isprovided. In this example, the force system 200 applies a force to thetissue layers 340 at a first time, t₁, when the dermis has a first meanz-axis thickness, th₁. Optionally and preferably, the analyzer 110acquires signals representative of the tissue layers 340 of the subject320 using the source system 400 and the detector system 500. Illustratedare three representative photon pathways, p₁₋₃, reaching the detectorsystem 500, such as at a first detector element, a second detectorelement, and a third detector element, respectively, at the first time,t₁, and/or within less than 60, 30, 15, 10, 5, or 1 second from thefirst time, t₁. Notably, at the first time, the first photon pathway,p₁, has an average path that does not penetrate into the dermis 346,while the second and third photon pathways, p₂₋₃, have mean pathwaysthat penetrate through the dermis into the subcutaneous fat 348. In atleast one preferred use of the analyzer, noninvasive glucoseconcentration determination is performed using a mean photon pathwaythat penetrates into the dermis 346 and not into the subcutaneous fat348 and/or uses signal from a detector element at a first/minimal radialdistance from the illumination zone, where the first/minimal radialdistance is the smallest radial distance observing an increase in a fatsignal/dominantly fat related signal, such as from the subcutaneous fat348, compared to a water signal/dominantly water related signal fromskin layers 340 closer to the skin surface 332 than that subcutaneousfat 348. Examples of wavelengths containing dominantly water absorbingsignals are wavelengths correlating with the peaks of the waterabsorbance bands 710, FIG. 7 , and examples of wavelengths containing anincreased fat absorbance to water absorbance ratio when a mean photonpath enters the subcutaneous fat 348 are at the fat absorbance bands720. Still referring to FIG. 6 , at a second time, t₂, the force wave250 from the force system 200 has expanded the dermis layer to a secondthickness, th₂, which is at least 0.1, 0.2, 0.3, 0.5, 1, 2, 5, 10, 20,or 50% thicker than the first thickness, th₁, and/or has an increasedwater absorbance, as measure by the first, second, and/or third detectorelement of the detector system 500, representative of the first throughthird photon pathway, p₁₋₃, in the condition of the larger dermisthickness at the second time, t₂, as represented by a fourth, fifth, andsixth photon pathway, p₄₋₆. Notably, the fifth and sixth photonpathways, p_(5,6), with the same illumination zone to detection zoneradial distance as the first and second photon pathways, p₁₋₂, have meanphoton pathways that penetrate into the dermis 346 and not into thesubcutaneous fat 348. Thus, the water-to-fat ratio of the observedsignal continues to increase with radial distance for the second andthird detectors after the force system 200 increased the thickness ofthe dermis 346 to the second thickness, th₂. Again, at least onepreferred measurement is a measurement with a higher water-to-fatabsorbance ratio. In this example, at the second time, the water-to-fatabsorbance ratio of the fifth optical path, p₅, is greater than observedwith the second optical path, p₂, despite have the same sourcezone-to-detector zone radial distance. Further, in this example apreferred optical signal is from the sixth optical path, th₆, at thesecond time, t₂, with a largest ratio of mean pathlength in the dermis346 to total mean detected pathlength.

Example II

Referring now to FIG. 8 , a second example is provided where theanalyzer 110 uses the force system 200 to alter the sample 300 toenhance a noninvasive analyte property determination using thespectrometer 140. As above, the force system 200 provides one or moreforce waves 250 into the subject 320, which alters positions of cells260 in the dermis 346 relative to the illumination zone of theillumination system 400 and or relative to one or more detection zonesassociated with a single element detector and/or one or more detectorsof an array of detector elements 510. As illustrated, the cells 360 havea first average intercellular distance at a first time, t₁, which isaltered by application of the force wave 250 to a second averageintercellular distance at a second time, t₂, where the net change incell position alters detected spectrophotometric absorbance signals at agive detector element of the detector system 500 by greater than 0.01,0.02, 0.05, 0.1, 0.5, 1, 2, 5, or 10 percent, such as by a change inobserved scattering and/or observed absorbance at a fixed radialdistance between an illumination zone and a detection zone. Similarly,the average percentage volume of the intercellular fluid 350 in thedermis layer differs by greater than 0.01, 0.02, 0.05, 0.1, 0.5, 1, 2,5, or 10 percent as a result of the applied force wave(s) 250. All of achange in thickness, change in observed mean pathlength, change inradial distance of detection, change in mean intercellular spacing,change in scattering, and change in water concentration, related toperfusion, are illustrated between the first time, t₁, and the secondtime, t₂, as a result of the applied force wave 250. Notably, a selecteddetector signal from the array of detectors 510 changed from a seconddetector element 512 at a first radial distance, r₁, from theillumination zone to a fourth detector element 514 at a second radialdistance, r₂, from the illumination zone based on the above describedlarger observed water signal-to-observed fat signal ratio and/or as thesecond pathlength, b₂, is longer than the first pathlength, b₁, in thedermis layer. Similarly, absorbances of skin constituents, such asprotein, albumin, globulin, keratin, and/or elastin increase relative tofat absorbance for the second pathlength, b₂, as the mean pathlengthspends more time in the dermis layer compared to the subcutaneous fatlayer 348, as described supra.

Example III

Referring now to FIG. 9 , a third example of using the force system 200to alter properties of the subject 330 to enhance performance of anoninvasive glucose concentration determination using the spectrometer140 is provided. In this example, the detector array 510 of the detectorsystem 500 contains n detector elements at differing radial distancesfrom a time correlated illumination zone. For clarity of presentation,the detector array 510 is illustrated with four detector elements: afirst detector element 511, a second detector element 512, a thirddetector element 513, and a fourth detector element 514. At a firsttime, t₁, the large water absorbance, protein absorbance, and/or proteinand water absorbance-to-fat ratio is observed using the second detectorelement 512 having a first illumination zone-to-detection zone radialdistance, r₁, and a first mean optical pathway, d₁, penetrating into thedermis 346 with minimal to no mean penetration into the subcutaneous fat348. However, at a second time, t₂, after the provided force wave 250has altered the skin of the subject 320, the third detector element isobserved, at a selected detection point in time, to have the largestmetric for detector selection, such as a smoothly falling observedintensity with radial distance at a fat absorbance wavelength, where asudden decrease in observed intensity at the fat absorbance wavelengthindicates mean penetration of the observed optical pathway into thesubcutaneous fat 348, such as at the second radial distance, r₂.Notably, the largest radial distance is selected for a given water,protein, and/or fat based metric as at the larger radial distance adifference between a shortest possible pathlength between theillumination zone and the detection zone, the radial distance, isclosest to the largest possible observed pathlength, which is based upona maximum observable absorbance by a detector type for a fixed number ofphotons. For example, if the maximum observable absorbance is 3.9 andthe absorbance per millimeter is 1.3, then a maximum observablepathlength is 3.0 mm. If the observed radial pathlength is 1.5 mm then afirst range of observed pathlengths is 1.5 to 3.0 mm with a differenceof 1.5 mm. Hence, a first ratio of observed pathlength difference toradial distance is 1:1 (1.5 mm:1.5 mm), which is a 100% error. However,if the observed radial pathlength is 2.5 mm, then a second range ofobserved pathlengths is 2.5 to 3.0 mm with a difference of 0.5 mm.Hence, a second ratio of observed pathlength difference-to-radialdistance is 1:5 (0.5 mm:2.5 mm), which is a second pathlength error of20% or one-fifth of the pathlength error of the first case. In general,the largest radial distance yielding and intensity-to-noise ratio beyonda threshold, such as 0.5, 1, 1.5 or 2, is preferred as error in a rangeof observed pathlengths decreases, which reduces the error in b, inBeer's Law: equation 1,A=molar absorptivity*b*C  (eq. 1)where b is pathlength and C is concentration, which is central tovisible and near-infrared absorbance and/or scattering models used todetermine an analyte property, such as a noninvasive glucoseconcentration as measured using photons optically probing skin.

Skin State Classification

Skin state is optionally classified using a single force pulse or singleimpulse function, also referred to herein as a ping. Generally, anapplied force, such as the force wave 250 provided by the force system200, takes time to propagate through the subject 320. The travel time ofthe force wave varies as a function of state of the body, such ashydration, temperature, glucose concentration, triglycerideconcentration, hematocrit and/or any constituent of skin, blood, and/orinterstitial fluid. Hence, the amount of time to travel radial distancesto force wave detectors is optionally used to classify the state of thesubject and/or to map the state of the subject in regions probed by theforce wave. For clarity of presentation and without loss of generality,two example of force wave detection are provided here using: (1) atransducer force detector and/or (2) an optical force wave classifier.

Example I

Referring now to FIGS. 10 (A-C), transducer force detectors areoptionally used to detect transit times of the force wave 250 from theforce wave input element 210 to one or more detectors of a set oftransducer force detectors 260. Generally, a transducer force detectorconverts mechanical motion, such as passage of the force wave 250 and/orskin movement into a measured electrical signal. Referring now to FIG.10A, for clarity of presentation and without loss of generality, a firsttransducer force detector 262, a second transducer force detector 264,and a third transducer force detector 266 are illustrated that representn transducer based force detectors, where n is a positive integer ofgreater than 1, 2, 3, 5, 10, or 20. As illustrated in FIGS. 10B and 10C,the n transducer based force detectors are optionally positioned in alinear array, in a two-dimensional array, and/or along arcs, such as atdiffering radial distances from one or more light sources in the sourcesystem 400. Referring still to FIG. 10A, as illustrated, at a firsttime, the force wave 250 has propagated to the first transducer forcedetector 262 as a first wave front position 254; at a second time, t₂,the force wave 250 has propagated to the second transducer forcedetector 264 as a second wave front position 256; and at a third time,t₃, the force wave 250 has propagated to the third transducer forcedetector 266 as a third wave front position 258. Timing of each wavefront to each transducer based force wave detector allows: (1)generation of a sub-surface tissue map of constituents of the skin ofthe subject 320 using mathematical techniques used for seismic mappingknown to those skilled in the art of seismic mapping and/or (2) aclassification of state of the subject 320 versus a calibration set ofclassifying states of force wave propagation radial translation times.For instance, the classification is as simple as slow, medium, or fasttranslation times to a given transducer detector or a more involvedcombination of translation times for one or more of: (1) responses at asingle detector position and (2) responses at a set of detectorpositions and/or responses to varying inputs of the force wave, such astime, direction, amplitude, and/or frequency of one or more pings fromthe force wave input elements and/or time varying induced appliedpressure and/or displacement of a portion of the skin of the subject 320by the force system 200.

Example II

Referring now to FIGS. 11 (A-C), propagation of the force wave(s) 250,such as force wave fronts 254, 256, 258 is detected using a set ofoptical detectors and using the results in a manner similar to detectingthe force wave 250 using the set of transducer based wave detectors. Forinstance, as the force wave 250 propagates through the tissue layers340, the density, absorbance, and/or scattering of voxels of the skin ofthe subject 320 change, which alters an observed mean optical pathbetween a given source of photons and a photon/photonic detector. One ormore sources of the source system 400 coupled to the array of opticaldetector elements 510 via the subject 320 is optionally used to detectpropagation times of the force wave(s) 250. For clarity of presentationand without loss of generality, a first optical detector 521, a secondoptical detector 522, and a third optical detector 523 are illustratedthat represent n optical detectors, where n is a positive integergreater than 0, 1, 2, 3, 5, 10, 15, 16, 20, 25, 100, 500, 1000, and5000. As illustrated in FIGS. 11B and 11C, the n optical detectors areoptionally positioned in a linear array, in a two-dimensional array,and/or along arcs, such as differing radial distances from one or morelight sources in the source system 400 and/or from one or more forcewave sources. Notably, one or more detectors of the array of opticaldetector elements 510 are optionally and preferably used to detectphotons from the source system 400 during a measurement phase of ananalyte and/or tissue property with or without a tissue classificationstep. As illustrated, the first optical detector 521 detects a firstoptical signal, modified by the force wave 250, with a first pathlength,p₁, at a given point in time; the second optical detector 522 detects asecond optical signal, modified by the force wave 250, with a secondpathlength, p₂, at the given point in time; and the third opticaldetector 523 detects a third optical signal, modified by the force wave250, with a third pathlength, p₃, at the given point in time. Eachdetected optical signal contains absorbances due to any sampleconstituent, such as water, protein, fat, and/or glucose and/or isrepresentative of state of the tissue, such as a measure of scatteringand/or temperature. As the force wave(s) propagate through the tissue,the first, second, and third pathlengths, p₁, p₂, p₃, vary. Hence, thestate of the subject 320 is optionally characterized and/or mapped in amanner similar to the transducer wave detection classification and/ormapping; however, optical signals with chemical meaning are used in theprocess, such as detected intensity, absorbance, and/or scatteringrelated to temperature, one or more tissue layer properties, collagen,elastin, water, albumin, globulin, protein, fat, hematocrit, and/orglucose, such as a concentration, change in tissue state, or a physicalstructure.

Referring again to FIG. 11A and FIG. 12A, the applied pressure/forcewave/displacement optionally generates a gap and/or varies an appliedpressure at a first interface 305 of the source system 400 and the skinsurface 330 and/or at a second interface 390 of the detector system 500and/or any element thereof and the skin surface 330. A resulting air gapbetween the analyzer 110 and the subject 320 and/or a time varyingchange between an air gap and contact between the analyzer 110 and thesubject 320 is used to determine times of contact/relative contact,which is in turn optionally and preferably used in a selection ofdetected signals step, described infra. For example, loss of opticalcontact yields a sudden increase in observed intensity in a wavelengthregion of high absorbance, such at as region dominated by waterabsorbance in the range of 1350 to 1550 nm, 1400 to 1500 nm, and/orwithin 5, 10, 15, 25, and/or 50 nm of 1450 nm. Removal of non-contactingsignals aids in the development of an outlier analysis algorithm and/orin determining state of the tissue and/or in determination of a degreeof applied force from the source system 400, detector system 500, and/oranalyzer 110 to the skin surface 330 of the subject 320 as a function oftime and/or position.

Force Wave/Optical Probe Analyte State Determination

Referring now to FIG. 12 , a process of determining an analyte property,such as a glucose concentration, using one or more optical signalsoptionally and preferably modified by an applied force, force wave,and/or displacement is provided.

Referring still to FIG. 12 , in a process, such as a first process or asecond process, a force is applied 1210, such as in the form of a forcewave and/or displacement induced force wave. For example, the forcewave/displacement is generated with a transducer to generate applicationof a transducer force 1212, which is a single ping 1214/displacementand/or a series of pings and/or is a force/displacement varied infrequency 1216 and/or varied in amplitude 1218, such as via acontroller, such as a main controller of the analyzer 110. Subsequently,the force wave 250/tissue displacement induced pressure propagates inthe sample 1220.

Referring still to FIG. 12 , in another process, such as a first orsecond process, a result of the tissue displacement induced force waveis measured and/or detected 1230, such as through a transducer forcedetection 1232 and/or an optical force detection 1234.

Referring still to FIG. 12 , in still another process, such as a secondand/or third process, selection of a sub-set of detected signals 1240 isperformed, such as a function of position 1241, time 1242, detector1243, contact 1244, pressure 1245, and/or spectroscopic response 1246and an analyte state is determined 1250, such as via generation of acalibration 1252 and/or use of a generated calibration in a predictionstep 1254.

Acousto-Optic Analyzer vs. (1) UPI and (2) an AOTF

An applied force-optic analyzer is described herein. Optionally andpreferably, the applied force results in a mechanical disturbance of thetissue resulting in a force being applied to the sample. However, in asub-case of the applied force-optic analyzer, the applied forcecomprises an acoustic force yielding an acousto-optic analyzer. Notably,in the sub-case of the applied force-optic analyzer being anacousto-optic analyzer, as used herein an acousto-optic analyzer starklycontrasts with both: (1) an ultrasonic photoacoustic imaging (UPI)system and (2) an acousto-optic tunable filter (AOTF) spectrometer, asdescribed infra.

Acousto-Optic Analyzer

As described, an acousto-optic analyzer (AOA) introduces an acousticvibration wave to the sample to impact the state of the sample, such astissue, and the state of the sample is measured using an optical probe.

Photoacoustic Imaging

In stark contrast, according to Wikipedia, ultrasonic photoacousticimaging, also referred to as (UPI), photoacoustic imaging (PI), and/oroptoacoustic imaging, delivers non-ionizing laser pulses to biologicaltissue, which results in absorbed energy and resultant heat in the formof transient thermoelastic expansions detected as wideband megaHertzultrasonic emissions detected by ultrasonic transducers. The detectedsignals are used to produce images. As optical absorbance relationshipsexist with physiological properties, such as hemoglobin concentrationand oxygen saturation, the detected pressure waves may be used todetermine hemoglobin and oxygen concentration.

Hence, an acousto-optic analyzer starkly contrasts with photoacousticimaging. Stated again, while the acousto-optic analyzer described hereinmay induce a heat wave like in photoacoustic imaging, in photoacousticimaging the sound wave is detected whereas photons, from an externalsource, are detected in the acousto-optic analyzer described aredetected after interacting with the sample beingdisplaced/heated/disturbed by the sound wave.

Acousto-Optic Tunable Filter

According to Wikipedia, an acousto-optic tunable filter (AOTF),diffracts light based on an acoustic frequency. By tuning the frequencyof the acoustic wave, the desired wavelength of the optical wave can bediffracted acousto-optically.

Hence, an acousto-optic analyzer (AOA) starkly contrasts with anacousto-optic tunable filter (AOTF) as, while the input sound wave ofthe AOA may diffract light, the separation of the input light is not theprimary use of the sound wave. Indeed, a narrow-band light emittingdiode (LED) is optionally used in conjunction with a broadband detectorin the acousto-optic analyzer making any separation of the narrow bandlight source pointless. Further, in the AOA, the sound wave is used tochange the state of the biological sample itself, whereas in the AOTFthe sound wave is introduced to a birefringent crystal in a wavelengthseparation module of the spectrometer and is not introduced into thesample.

Still yet another embodiment includes any combination and/or permutationof any of the elements described herein.

The main controller, a localized communication apparatus, and/or asystem for communication of information optionally comprises one or moresubsystems stored on a client. The client is a computing platformconfigured to act as a client device or other computing device, such asa computer, personal computer, a digital media device, and/or a personaldigital assistant. The client comprises a processor that is optionallycoupled to one or more internal or external input device, such as amouse, a keyboard, a display device, a voice recognition system, amotion recognition system, or the like. The processor is alsocommunicatively coupled to an output device, such as a display screen ordata link to display or send data and/or processed information,respectively. In one embodiment, the communication apparatus is theprocessor. In another embodiment, the communication apparatus is a setof instructions stored in memory that is carried out by the processor.

The client includes a computer-readable storage medium, such as memory.The memory includes, but is not limited to, an electronic, optical,magnetic, or another storage or transmission data storage medium capableof coupling to a processor, such as a processor in communication with atouch-sensitive input device linked to computer-readable instructions.Other examples of suitable media include, for example, a flash drive, aCD-ROM, read only memory (ROM), random access memory (RAM), anapplication-specific integrated circuit (ASIC), a DVD, magnetic disk, anoptical disk, and/or a memory chip. The processor executes a set ofcomputer-executable program code instructions stored in the memory. Theinstructions may comprise code from any computer-programming language,including, for example, C originally of Bell Laboratories, C++, C#,Visual Basic® (Microsoft, Redmond, Wash.), Matlab® (MathWorks, Natick,Mass.), Java® (Oracle Corporation, Redwood City, Calif.), andJavaScript® (Oracle Corporation, Redwood City, Calif.).

Herein, any number, such as 1, 2, 3, 4, 5, is optionally more than thenumber, less than the number, or within 1, 2, 5, 10, 20, or 50 percentof the number.

Herein, an element and/or object is optionally manually and/ormechanically moved, such as along a guiding element, with a motor,and/or under control of the main controller.

The particular implementations shown and described are illustrative ofthe invention and its best mode and are not intended to otherwise limitthe scope of the present invention in any way. Indeed, for the sake ofbrevity, conventional manufacturing, connection, preparation, and otherfunctional aspects of the system may not be described in detail.Furthermore, the connecting lines shown in the various figures areintended to represent exemplary functional relationships and/or physicalcouplings between the various elements. Many alternative or additionalfunctional relationships or physical connections may be present in apractical system.

In the foregoing description, the invention has been described withreference to specific exemplary embodiments; however, it will beappreciated that various modifications and changes may be made withoutdeparting from the scope of the present invention as set forth herein.The description and figures are to be regarded in an illustrativemanner, rather than a restrictive one and all such modifications areintended to be included within the scope of the present invention.Accordingly, the scope of the invention should be determined by thegeneric embodiments described herein and their legal equivalents ratherthan by merely the specific examples described above. For example, thesteps recited in any method or process embodiment may be executed in anyorder and are not limited to the explicit order presented in thespecific examples. Additionally, the components and/or elements recitedin any apparatus embodiment may be assembled or otherwise operationallyconfigured in a variety of permutations to produce substantially thesame result as the present invention and are accordingly not limited tothe specific configuration recited in the specific examples.

Benefits, other advantages and solutions to problems have been describedabove with regard to particular embodiments; however, any benefit,advantage, solution to problems or any element that may cause anyparticular benefit, advantage or solution to occur or to become morepronounced are not to be construed as critical, required or essentialfeatures or components.

As used herein, the terms “comprises”, “comprising”, or any variationthereof, are intended to reference a non-exclusive inclusion, such thata process, method, article, composition or apparatus that comprises alist of elements does not include only those elements recited, but mayalso include other elements not expressly listed or inherent to suchprocess, method, article, composition or apparatus. Other combinationsand/or modifications of the above-described structures, arrangements,applications, proportions, elements, materials or components used in thepractice of the present invention, in addition to those not specificallyrecited, may be varied or otherwise particularly adapted to specificenvironments, manufacturing specifications, design parameters or otheroperating requirements without departing from the general principles ofthe same.

Although the invention has been described herein with reference tocertain preferred embodiments, one skilled in the art will readilyappreciate that other applications may be substituted for those setforth herein without departing from the spirit and scope of the presentinvention. Accordingly, the invention should only be limited by theClaims included below.

The invention claimed is:
 1. An apparatus for noninvasively determiningan analyte property of a subject having skin and skin layers,comprising: an electro-mechanical transducer affixed to the skin of thesubject; a controller, said controller providing a voltage waveform tosaid electro-mechanical transducer driving displacement of the skin andinducing a pressure wave into the skin; and a spectrometer interfaced toa sample site of the skin, said spectrometer comprising a set of sourcesand a set of detectors, said controller configured to collect signalfrom said set of detectors as a function of timing of said voltagewaveform and apply a calibration model to the signal to determine theanalyte concentration.
 2. The apparatus of claim 1, saidelectro-mechanical transducer comprising: at least one piezo-electricmaterial configured to convert the voltage waveform into mechanicalmovement against the skin resulting in the displacement of the skin. 3.The apparatus of claim 1, said electro-mechanical transducer comprising:a motor rotating an off-center mass around an axis.
 4. The apparatus ofclaim 1, further comprising: a double-sided adhesive, said double-sidedadhesive affixing said electro-mechanical transducer to the skin.
 5. Theapparatus of claim 1, further comprising: an analyzer comprising saidelectro-mechanical transducer, said controller, said spectrometer, andan interface zone, at least one of said set of sources coupling photonsthrough a fluorocarbon, embedded in a flexible material covering atleast a portion of said interface zone, and into the skin.
 6. Theapparatus of claim 5, said flexible material further comprising: anadhesive surface, said adhesive surface configured to temporarily affixsaid analyzer to the skin of the subject.
 7. The apparatus of claim 1,further comprising: a first detection transducer at a first radialdistance from the sample site, said controller configured to use anelectric signal from said first detection transducer, induced in saidfirst detection transducer by the pressure wave in the skin, todetermine a transport time from said electro-mechanical transducer tosaid first detector and to classify the subject with the transport time.8. The apparatus of claim 1, further comprising: a first detectiontransducer contacting the skin at a first radial distance from thesample site; and a second detection transducer contacting the skin at asecond radial distance from the sample site.
 9. A method fornoninvasively determining an analyte property of a subject having skinand skin layers, comprising the steps of: affixing an electro-mechanicaltransducer to the skin of the subject; a controller driving saidelectro-mechanical transducer with a voltage waveform to inducedisplacement of the skin and generate a pressure wave in the skin; aspectrometer collecting a near-infrared optical signal, saidspectrometer interfaced to a sample site of the skin, said spectrometercomprising a set of sources and a set of detectors; a controllercollecting a set of signals from said set of detectors as a function oftiming of said voltage waveform; and applying a calibration model toselected signals from the set of signals to determine the analyteconcentration.
 10. The method of claim 9, further comprising the stepof: selecting the selected signals as a function of time of peaks ofsaid voltage waveform.
 11. The method of claim 9, further comprising thestep of: selecting the selected signals as a function of detected signalfrom a dermis layer of the skin layers.
 12. The method of claim 9,further comprising the step of: selecting the selected signals as afunction of time of transport of the pressure wave in the skin to adetector of said set of detectors.
 13. The method of claim 9, said stepof displacing further comprising the step of: said electro-mechanicaltransducer applying said pressure wave as an analog varying waveresponsive to said voltage waveform repeating with a frequency and anamplitude.
 14. The method of claim 13, further comprising the step of:selecting the selected signals as a function of time of transport of thepressure wave in the skin to a detector of said set of detectors.
 15. Anapparatus for noninvasively determining an analyte property of a subjecthaving skin and skin layers, comprising: an analyzer comprising: anelectro-mechanical transducer configured to displace skin of the subjectgenerating a force wave propagating into the skin layers; anear-infrared spectrometer, comprising: a set of sources; a set ofdetectors; and coupling optics, configured to couple photons from saidset of sources to said set of detector via the skin layers of thesubject; and a controller configured to drive said electro-mechanicaltransducer and select responses from said set of detectors as a functionof timing of operation of said electro-mechanical transducer.
 16. Theapparatus of claim 15, said apparatus further comprising: a housing,both said electro-mechanical transducer and said spectrometer at leastpartially embedded in said housing.
 17. The apparatus of claim 16,further comprising: an adhesive layer affixed to said housing, anadhesive side of said adhesive layer configured to removably attach saidhousing to the skin of the subject.
 18. The apparatus of claim 17,further comprising: a fluorocarbon embedded into said adhesive.